Women are predominantly affected by irritable bowel syndrome (IBS). The reason for this prevalence is not yet established. Evidence supports the presence of sex-dependent immune activation in the colon that plays role in alterations of visceral sensitivity and epithelial functions. In women with IBS, a higher number of activated mast cells are present than in men with IBS. Despite these, the possibility of sex differences in the alterations of colonic mucosal neuroimmune functions in relation with abdominal pain and constipation symptoms in IBS patients has not been investigated. Based on preliminary data in rats exposed to repeated stress showing sex-specific alterations of visceral pain and epithelial functions, the overall goal of this proposal is to establish the influence of sex hormones on stress-induced alterations of sensory and epithelial functions and determine the mechanisms by which sex hormones both under basal and stress conditions modulate colonic epithelial physiology and subsequently visceral pain responses. The proposed studies intend to provide a better understanding of sex differences in the expression of visceral pain in relationship with alterations of the gastrointestinal epithelial function. The findings should have significant implications for translational research and the development of sex- specific treatments, thereby improving health care for IBS patients. The candidate has a long-standing interest in sex-related biological differences and her current research has focused on altered peripheral pathways in the modulation of visceral pain in rodent models of IBS. The candidate's long term goals include becoming established in the field of epithelial physiology research. The career development plan will focus on developing a broad-based and in depth understanding of sex biology and epithelial physiology as they relate to visceral pain and constipation through didactic and mentored training. The candidate will be mentored by Dr. Paul Micevych, Professor in the Department of Neurobiology at UCLA and expert in the sex steroids field, in particular in the cellular and molecular events underlying estrogen's profound effects on pain. In addition, the candidate has co- mentors at UCLA and UCSD faculty members with expertise in sex chromosome and hormone differences and pain (Dr. Art Arnold), intestinal epithelial physiology (Dr. Kim Barrett), IBS neuroendocrine and peripheral clinical studies (Dr. Lin Chang) and stress and neurogastroenterology (Dr. Yvette Tachi). The central hypothesis of this proposal is that the higher susceptibility of females to visceral pain and constipation is related to sex-specific alterations of the immune (mast cells) and epithelial (ion channels and secretion, tight junctions and permeability) systems related to sex hormones. The hypothesis will be tested in the following specific aims. In Aim 1, we will dissect the role of gonadal hormones and sex chromosome complements in the sex difference in stress-induced visceral hyperalgesia and examine the influence of gonadal hormones on the recruitment and activity of colonic mucosal mast cells. In Aim 2, we will dissect the influence of sex chromosome and gonadal hormones on the sex- specific stress-induced alterations colonic epithelial permeability/secretion in female rats by assessing the modulatory effect of ovarian hormones on epithelial cells via tight junctions proteins modulation/permeability and on ion channels/secretion and on mast cells release of chymase and subsequent increase in angiotensin II leading to a reduction in ion secretion. Together, the proposed studies will enhance knowledge on interactions existing between sex and neuroimmune mucosal functions influencing pain sensitivity and secretion in IBS and enable the candidate to propose new testable hypotheses regarding mechanisms of IBS pain and constipation, in particular regarding differential treatment approaches based on pathophysiology and sex differences PUBLIC HEALTH RELEVANCE: The long term goal of this proposal is to improve treatment strategies for patients with irritable bowel syndrome (IBS), by providing a better understanding of sex differences and the influence of sex hormones in neuroimmune epithelial dysfunctions and associated alterations of visceral pain and secretion contributing to IBS pathophysiology.